TY - JOUR
T1 - Tumor-reprogrammed resident T cells resist radiation to control tumors
AU - Arina, Ainhoa
AU - Beckett, Michael
AU - Fernandez, Christian
AU - Zheng, Wenxin
AU - Pitroda, Sean
AU - Chmura, Steven J.
AU - Luke, Jason J.
AU - Forde, Martin
AU - Hou, Yuzhu
AU - Burnette, Byron
AU - Mauceri, Helena
AU - Lowy, Israel
AU - Sims, Tasha
AU - Khodarev, Nikolai
AU - Fu, Yang Xin
AU - Weichselbaum, Ralph R.
N1 - Funding Information:
We thank Rolando Torres and Ani Solanki for technical assistance, as well as Jorge Andrade and Li Yan (Bioinformatics Core), Mihai Giurcanu (Biostatistics Lab), Christine Labno and Vytas Bindokas (Integrated Light Microscopy Core), Pieter Faber (Genomics Facility), David Leclerc (Cytometry and Antibody Technology) at the University of Chicago. We also thank Dr. Hans Schreiber for the donation of materials and mice; Carlos Martinez for help with the bioinformatics analysis; Laura Mackay, Peter Savage, Richard Hynes, Brendan MacNabb, Hua Liang, Meng Xu, and Samuel Hellman for helpful discussions, and Amy K. Huser for editorial help. This work was supported by funds from the Ludwig Foundation for Cancer Research and from Regeneron Pharmaceuticals.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Successful combinations of radiotherapy and immunotherapy depend on the presence of live T cells within the tumor; however, radiotherapy is believed to damage T cells. Here, based on longitudinal in vivo imaging and functional analysis, we report that a large proportion of T cells survive clinically relevant doses of radiation and show increased motility, and higher production of interferon gamma, compared with T cells from unirradiated tumors. Irradiated intratumoral T cells can mediate tumor control without newly-infiltrating T cells. Transcriptomic analysis suggests T cell reprogramming in the tumor microenvironment and similarities with tissue-resident memory T cells, which are more radio-resistant than circulating/lymphoid tissue T cells. TGFβ is a key upstream regulator of T cell reprogramming and contributes to intratumoral Tcell radio-resistance. These findings have implications for the design of radio-immunotherapy trials in that local irradiation is not inherently immunosuppressive, and irradiation of multiple tumors might optimize systemic effects of radiotherapy.
AB - Successful combinations of radiotherapy and immunotherapy depend on the presence of live T cells within the tumor; however, radiotherapy is believed to damage T cells. Here, based on longitudinal in vivo imaging and functional analysis, we report that a large proportion of T cells survive clinically relevant doses of radiation and show increased motility, and higher production of interferon gamma, compared with T cells from unirradiated tumors. Irradiated intratumoral T cells can mediate tumor control without newly-infiltrating T cells. Transcriptomic analysis suggests T cell reprogramming in the tumor microenvironment and similarities with tissue-resident memory T cells, which are more radio-resistant than circulating/lymphoid tissue T cells. TGFβ is a key upstream regulator of T cell reprogramming and contributes to intratumoral Tcell radio-resistance. These findings have implications for the design of radio-immunotherapy trials in that local irradiation is not inherently immunosuppressive, and irradiation of multiple tumors might optimize systemic effects of radiotherapy.
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U2 - 10.1038/s41467-019-11906-2
DO - 10.1038/s41467-019-11906-2
M3 - Article
C2 - 31477729
AN - SCOPUS:85071756189
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3959
ER -